Gut Microbiota-Derived Short-Chain Fatty Acids: Novel Regulators of Intestinal Serotonin Transporter

Area of Science:

• Neurogastroenterology and Gut Microbiome Research
• Molecular and Cellular Biology
• Neuroscience and Neuropharmacology

Background:

• Serotonin (5-HT) is a crucial neurotransmitter in both the central nervous system and the gut, influencing mood, cognition, and gastrointestinal functions.
• Serotonin transporter (SERT) regulates extracellular serotonin levels, impacting its signaling through various serotonin receptors (5-HTRs).
• Gut microbiota can influence serotonergic signaling, but the specific role of microbial metabolites like short-chain fatty acids (SCFAs) remains unclear.

Purpose of the Study:

• To investigate the effects of SCFAs, produced by gut microbiota, on the gastrointestinal serotonergic system.
• To determine if SCFAs modulate the function and expression of the serotonin transporter (SERT) and specific serotonin receptors (5-HTRs) in intestinal cells.

Main Methods:

• Utilized the Caco-2/TC7 cell line, which constitutively expresses SERT and various 5-HTRs.
• Treated cells with different concentrations of SCFAs (propionate, acetate, butyrate).
• Evaluated SERT function and expression, alongside the expression of 5-HT receptors 1A, 2A, 2B, 3A, 4, and 7.

Main Results:

• Microbiota-derived SCFAs, individually and in combination, were shown to regulate the intestinal serotonergic system.
• SCFAs modulated both the function and expression of SERT.
• Significant modulation of 5-HT receptor expression, specifically 5-HT1A, 5-HT2B, and 5-HT7, was observed.

Conclusions:

• Gut microbiota metabolites (SCFAs) play a direct role in modulating the intestinal serotonergic system.
• These findings highlight the gut microbiota's influence on intestinal homeostasis.
• Microbiome modulation presents a potential therapeutic avenue for intestinal pathologies and neuropsychiatric disorders linked to serotonin dysregulation.